We have found that adenoviral overexpression of BDNF in the adult rodent ventricular system induces the recruitment of new striatal neurons from the progenitor cell pool of the forebrain subependyma. The new striatal neurons project to the globus pallidus and adopt a DARPP32/GABAergic/calbindin+ phenotype, characteristic of medium spiny projection neurons. This is the major neostriatal phenotype lost in Huntington's Disease (HD);as such, the induced regeneration of these cells may be a feasible strategy for moderating disease progression. We also noted that the numbers of new neurons recruited to the striatum in response to BDNF could be greatly potentiated by suppressing gliogenesis, using adenoviral overexpression of noggin, a soluble antagonist of the pro-gliogenic bone morphogenetic proteins (BMPs). On this basis, this proposal asks if induced striatal neuronal recruitment might offer therapeutic benefit in murine models of Huntington's Disease. We have already noted that the R6-2 mouse, a transgenic model of Huntington's disease, indeed harbors competent striatal progenitor ceils, that these give rise to striatal neurons in response to intraventricular AdBDNF, and this process is potentiated by AdNoggin. On this basis, we now ask: 1) Does spontaneous neuronal recruitment occur in HD mice, in response to striatal neuronal loss? Are new neurons recruited in response to striatal apoptosis? What cellular and molecular signals elicit neuronal recruitment? 2) What is the lifespan and connectivity of AdBDNF/Noggin-induced striatal neurons in R6-2 nice? As what transmitter and functional phenotypes do these neurons integrate? 3) Does AdBDNF/AdNoggin-induced neuronal addition prolong the survival of R6-2 mice? Does it slow their motor deterioration? To what extent is AdBDNF/Noggin's effect due to neuronal addition, as opposed to AdBDNF-dependent neuroprotection'? Can the survival of BDNF/noggin-treated R6-2 mice be further improved by histone deacetylase inhibition, as a potentially synergistic neuroprotective strategy? 4) Is sustained BDNF and noggin expression required to maintain neuronal recruitment at levels sufficient to compensate for loss due to Huntington's disease? With what vector systems might this best be accomplished? Does the striatal progenitor pool deplete with sustained stimulation? 5) Can noggin and BDNF be used to induce meaningful levels of neuronal recruitment in the adult primate? Can AdBDNF/AdNoggin-treatment mediate the replacement of striatal neurons lost following treatment with ibotenic acid (IA)? If successful, these experiments should provide both a conceptual and operational foundation for the evaluation of induced striatal neurogenesis as a therapeutic strategy in Huntington's Disease, while providing new insight into the mechanistic bases for both compensatory and induced neurogenesis in the adult mammalian brain.